[8], who additionally showed that a minigene construct carrying the learn more c variant at position c.−21, when transfected to Hep G2 and Hep 3B cell lines, yielded a consistently weak RT-PCR product lacking exon 2, together with a strong full-length fragment. Nevertheless, this polymorphism is in a non-coding region of the gene and is quite rare with frequency of about 8% in heterozygotes in the general population [7–9], which could explain a more severe

phenotype in a minority of HAE patients. It seems likely that genetic factors outside of the SERPING1 gene play a substantial role as disease modifiers. Both complement and contact system activation take place in angiooedema development. Two molecules, a peptide derived from the C2 component of complement and bradykinin,

have been suspected to mediate HAE symptoms. Different lines of evidence now favour bradykinin to be the primary mediator of angiooedema [10]. Significantly selleck products increased levels of bradykinin concentration in the plasma of HAE patients during attacks were detected as compared to asymptomatic periods [11], and this difference was even more evident if the blood sample was taken from the site of oedema [12]. Moreover, another study has shown that bradykinin-mediated increase in vascular permeability in C1 Inh-deficient mice is facilitated by B2 bradykinin receptors [13]. Becasue of the evidence given previously, the B2 bradykinin receptor (BDKR2) gene was examined as one of the candidate genes, the product of which might influence the clinical manifestation of HAE [14]. A hypothesis was formulated that a polymorphic variant with a 9-bp deletion in the first exon of the BDKR2 gene, which has a higher expression in comparison with the variant without the deletion, facilitates

oedema manifestation in HAE patients [14]. However, no effect of this polymorphism on the clinical manifestation of HAE was reported in our group of patients [15]. Nevertheless, this finding does not exclude other bradykinin receptor (BDKR) genes’ polymorphisms to modify the course of the disease. The role of bradykinin B1 and B2 receptors (B1R, B2R) in the pathogenesis of other diseases has been described repeatedly [16, 17]. Another disease modifier may be the angiotensin-converting Tau-protein kinase enzyme (ACE), which is known to inactivate bradykinin. The deletion/insertion (D/I) polymorphism in the 16th exon of the angiotensin 1 converting enzyme (ACE) gene has been shown to modulate bradykinin metabolism in vivo in humans, when the D variant increased bradykinin degradation in comparison with the I variant [18]. Also relevant to our analysis, becasue of its participation in the complement activation pathway, is a potential role of mannose-binding lectin (MBL) in HAE pathogenesis. Recently, a strong correlation between MBL levels and activity of the lectin pathway was described in both HAE patients and healthy controls [19].